Neurotransmitters relay, amplify and/or modulate electrical signals between a neuron and adjacent neurons. Monoamine neurotransmitters include the catecholamines, such as norepinephrine [4-(2-amino-1-hydroxyethyl)benzene-1,2-diol] and dopamine [4-(2-aminoethyl)benzene-1,2-diol]; serotonin (5-hydroxytryptaminne, 5-HT); and histamine [2-(3H-imidazol-4-yl)ethanamine].
It is believed that many clinical conditions arise, at least in part, from a neurotransmitter imbalance. Serotonin regulates many physiological processes via activation of at least one of its 14 distinct receptors that are organized into 7 subfamilies. An imbalance in serotonergic neurotransmission in the central nervous system (CNS) is likely associated with mental illnesses, including depression, anxiety, schizophrenia, eating disorders, obsessive compulsive disorder (OCD) and migraines.
Selective serotonin reuptake inhibitors (SSRIs) increase the synaptic level of serotonin by inhibiting the serotonin-specific transporters to prevent re-entry of serotonin into its nerve terminals or neurons, thus increasing the serotonin available to bind to the postsynaptic receptors. SSRIs show less affinity for other monoamine transporters. SSRIs are first choice therapeutics for treating depression, certain forms of anxiety and social phobias and typically are tolerated better by subjects compared to classic tricyclic antidepressants.
While the serotonergic system modulates mood, the norepinephrinergic system modulates drive and energy. Drugs, including the secondary-amine-containing tricyclic antidepressants, desipramine and nortryptyline that affect mainly the norepinephrinergic system, have been available for some time.
Norepinephrine and serotonin receptors are known to interact anatomically and pharmacologically. Compounds that affect only serotonin exhibit modulatory effects on norepinephrine, pointing toward an important relationship between the two neurotransmitter systems. Duloxetine [(+)-N-methyl-3-(1-naphthalenyloxy)-2-thiophenepropanamine hydrochloride] inhibits both norepinephrine and serotonin reuptake. U.S. Pat. Nos. 4,956,388 and 5,023,269. Duloxetine (Cymbalta®) currently is being approved for the treatment of depression, diabetes peripheral neuropathic pain, general anxiety disorder, and urinary incontinence.
Efficacy and tolerability are important factors that determine the choice of a therapeutic. Older tricyclic antidepressants (TCAs) are associated with significant cognitive impairment and sedation. SSRIs are largely devoid of these effects, but gastrointestinal disturbances such as nausea and dyspepsia are common (Hindmarch I., 1997, Human Psychopharmacology, 12:115 119). For example, for the widely prescribed SSRI sertraline [(1S)-cis-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-napthalenamine] (Zoloft®, Pfizer, Inc.) the top three adverse events associated with discontinuation of treatment were nausea, insomnia and diarrhea (Physician's Desk Reference, 57th Edition, 2003, Thomson Medical).
It is difficult to predict chemical structure that will provide both a desired therapeutic activity and subject tolerance. Therefore a variety of therapeutics is needed to treat the full range of maladies associated with neurotransmitter modulation and/or imbalance. The present disclosure concerns new compounds, primarily embodiments having a cyclopropane ring, that are effective therapeutics. Applicants are aware of only one known dual serotonin and noradrenaline uptake inhibitor having a cyclopropane ring, namely milnacipran, which is shown below.
See, Wong et al., “Dual Serotonin and Noradrenaline Uptake Inhibitor Class of Anti-depressants—Potential for Greater Efficacy or Just Hype,” Progress in Drug Research, 58, 169-222 (2002). Thus, despite these known compounds, there still is a need to develop additional compounds that ameliorate or eliminate the disadvantages of known neurotransmitter therapeutics.